Biology Reference
In-Depth Information
hearing loss.
KCNQ4
encodes a potassium channel expressed in the outer
hair cells of the cochlea. Mutations of
KCNQ4
do co-segregate with dom-
inant, progressive deafness in Dutch, Belgian and United States families.
Linkage analyses of these families define the
DFNA2
interval (Coucke
et al. 1999). In a small pedigree with dominant, progressive, nonsyndromic
deafness, a missense mutation (G258S) was reported that exerts a dominant
negative effect on the wild-type
KCNQ4
allele and affects endolymph
potassium secretion (Kubisch et al. 1999).
Phenocopies were noted in two of the
DFNA2
families (Van Camp et al.
1997b). These individuals were omitted from genetic analyses to map the
responsible genes. It is critical to identify phenocopies early in a mapping
study, since even one unrecognized phenocopy in a large family may con-
found a positional cloning strategy to identify the gene.
3.4 DFNA3
GJB6
(connexin 30,
Cx30
) is another member of the large b-class family of
gap-junction proteins that mediate intercellular communication.
GJB6
is
closely linked to
GJB2
on chromosome 13q12, and many
GJB2
mutations
causing nonsyndromic hearing loss have been identified (see
DFNB1
). Con-
nexin 30 is expressed in the cochlea (Lautermann et al. 1998) and is struc-
turally similar to connexin 26. Moreover, there are families with deafness
linked to 13q12, but without mutations in
GJB2
. Thus, screening for muta-
tion in
GJB6
is a logical experiment. However, Kelley and co-workers
(Kelley et al. 1999) did not find mutations in
GJB6
in 23 dominant and 88
recessive nonsyndromic hearing-loss families, although these families are
presumably too small for linkage analyses.
In a small Italian family with three individuals showing a pattern of dom-
inant inheritance of progressive high frequency hearing loss, a missense
mutation (T5M) was reported in the three affected individuals (Grifa
et al. 1999). A convincing argument is yet to be made because this family
is small. The T5M variant did not induce electrochemical coupling between
cells when expressed in Xenopus oocytes. This assay, however, may not
always be a reliable indicator of in vivo function. For example, the M34T
allele of
GJB2
also has a low level of coupling in the Xenopus oocyte assay,
yet there is an individual who is compound-heterozygous for M34T, and a
null allele (167delT) who has essentially normal hearing (Griffith et al.
2000a).
3.5 Genetics and Identification of DFNA5
Van den Wijngaart described a Dutch family in which 105 members had
highly variable, progressive high-frequency hearing loss, with an age of
onset between 5 and 15 years and an autosomal-dominant pattern of inher-
itance (van den Wijngaart et al. 1985). The gene was initially mapped to a
